CORE B- SUMMARY/ABSTRACT Alzheimer?s Disease (AD) pathology is heterogenous, yet a comprehensive understanding of the different pathways that drive AD pathology is missing. The role of core B is to provide an unbiased characterization of proteins and pathways affected by different apoE isoforms in AD pathogenesis and therapeutic approaches targeting this role. Core B will provide well characterized human post mortem tissue from the NYU brain bank and post mortem tissue received from the Rush Alzheimer?s Disease Center (RADC). Core B will provide the unbiased characterization of the proteome of neuropathological lesions (parenchymal and vascular amyloid) using our recently established approach of localized proteomics - Laser Capture Microdissection (LCM) followed by label-free quantitative mass spectrometry (LC-MS). The samples consist of tissues collected from patients with AD who are apoE4, apoE3 or apoE2 carriers that have the full spectrum of AD (preclinical cognitive normal, mild cognitive impairment (MCI) and AD), and AD transgenic mice models that express human ApoE 2,3 or 4 isoforms. In addition, the core will verify the peptoids and small drugs used in Project 2 by mass spectrometry prior to injection into mice. This core will provide a single state of the art analytical mass spectrometry platform that will be used across all for 3 projects. This key feature will ensure that the acquired data is reproducible and facilitates the downstream analysis of correlating the findings of all 3 projects. The specific aims of the Core are: 1. Provide human brain tissue characterized using standardized state-of-the-art neuropathological analysis (Projects 1 and 3) 2. Characterize and quantify the amyloid plaque and cerebral amyloid angiopathy (CAA) proteomes of preclinical cognitive normal, MCI, and late AD of apoE4, apoE3 and apoE2 carriers (Proje ct 1). 3. Characterize A? and phosphorylated tau binding proteins using affinity purifications followed by MS (Project 1). 4. Characterize the amyloid plaque and CAA proteomes in transgenic mice expressing apoE2, apoE3, apoE4 or apoE KO, with and without treatment (peptoid, small molecule drugs) (Proje ct 2). 5. Verify that the therapeutic antibodies developed in Project 3 cross the blood brain barrier (Proje ct 3). 6. Characterize the effect of passive immunotherapy with IgM and IgG A?ComAbs on the CAA proteome in TgSwDI, 3xTg, APP/PS1 mice crossed onto an apoE2, E3 and E4 background (Proje ct 3). The proteomic data generated by Core B will facilitate greater understanding of apoE?s role in the pathogenesis of AD and will aid the discovery of proteins and pathways involved in the development of AD. Importantly, the combined use of human tissue and AD animal models will enhance the translatability of the findings to clinical practice.